AB0132 AFIMETORAN (BMS-986256), AN EQUIPOTENT TLR7/8 ANTAGONIST, DEMONSTRATES STEROID-SPARING EFFECTS IN A LUPUS MOUSE MODEL
Authors: S. Dudhgaonkar, P. Chopra, A. Rudra, S. Subramani, S. Palachandra, N. Bhatt, V. Pabbala, S. Ranade, D. S. P. Ega, A. Dyckman, Q. Zhao
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with extensive heterogeneity in disease presentation due to an underlying molecular diversity of dysregulated pathways. Glucocorticoids, like prednisolone, are part of the standard-of-care treatment for SLE. However, over time, patients develop resistance to glucocorticoid therapies, and steroid resistance is an important unmet need for patients with SLE. Furthermore, patients can experience side effects, which make long-term use undesirable. Toll-like receptors (TLR) 7 and 8 are endosomal receptors that play a key role in innate immunity. TLR7 and 8 are expressed in various immune cells where they recognize single-stranded RNA and initiate downstream signaling via the Nuclear Factor kappa B (NFkB) and interferon regulatory factor pathways. Activation of the NFkB pathway contributes to the resistance to steroids, and its activation via TLR7 and 8 pathways, along with inhibition of plasmacytoid dendritic cell (pDC) apoptosis via TLR7, could be a driving factor leading to steroid resistance. <h3>Objectives</h3> To evaluate the steroid-sparing potential of afimetoran, an equipotent, dual antagonist of TLR7 and TLR8, currently in clinical development for SLE and cutaneous lupus erythematosus. <h3>Methods</h3> NZB/W mice with moderate disease (proteinuria of 60–100 mg/dL) were treated therapeutically once daily with vehicle or selected doses of afimetoran and/or prednisolone. Survival, kidney injury, splenomegaly, age-associated B-cells (ABCs, measured by CD19, T-bet, and CD11c positivity), serum auto-antibody titers (anti-double stranded DNA antibodies, anti-nuclear antibodies [anti-Smith, anti-ribonucleoprotein, anti–Sjögren's-syndrome-related antigen A autoantibodies]), and plasma interleukin-12p40 (IL-12p40) were assessed in all treatment groups. To assess the impact of afimetoran on the effect of steroids on TLR7 activation in vitro, C57 wild-type mouse bone marrow cells (BMCs) were challenged with the TLR7 agonist gardiquimod and treated with prednisolone alone, or in combination with afimetoran. Both for C57 wild-type BMCs treated in vitro and NZB/W BMCs from mice dosed orally, B-cell and pDC apoptosis was evaluated by annexin V staining using flow cytometry. <h3>Results</h3> In the NZB/W mouse model, afimetoran improved survival when used alone or in combination with prednisolone. It also significantly and dose-dependently suppressed kidney injury markers such as proteinuria, neutrophil gelatinase-associated lipocalin (NGAL), and tissue inhibitor of metalloproteinases 1 (TIMP1). Splenomegaly and suppression of ABCs were improved, particularly when afimetoran was combined with prednisolone. Significant and dose-dependent suppression of plasma IL-12p40 and serum auto-antibody titers was also observed in all active treatment groups, demonstrating the potential of afimetoran in this mouse model of SLE. An improved steroid response was seen in gardiquimod-stimulated mouse BMCs collected from C57BL/6 mice and exposed in vitro to afimetoran, which showed a significant increase in prednisolone-induced apoptosis of pDCs and B cells compared to baseline control or prednisolone alone. A similar trend was seen in vivo for BMCs collected from NZB/W mice dosed with combinations of afimetoran and prednisolone. <h3>Conclusion</h3> Afimetoran, either alone or in combination with prednisolone, showed efficacy in NZB/W mice with moderate disease. It also reversed the resistance of bone marrow pDCs and B cells to prednisolone-induced apoptosis. These data confirm that afimetoran, an equipotent TLR7/8 antagonist, has the clinical potential to be steroid-sparing. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Shailesh Dudhgaonkar Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Puneet Chopra Employee of: Syngene, Anjuman Rudra Employee of: Syngene, Siva Subramani Employee of: Syngene, Sourabha Palachandra Employee of: Syngene, Nikita Bhatt Employee of: Syngene, Veeresh Pabbala Employee of: Syngene, Sourabh Ranade Employee of: Syngene, Durga Shiva Prasad Ega Employee of: Syngene, Alaric Dyckman Employee of: Bristol Myers Squibb, Qihong Zhao Employee of: Bristol Myers Squibb.